A computer aided treatment event recognition system in radiation therapy.
To develop an automated system to safeguard radiation therapy treatments by analyzing electronic treatment records and reporting treatment events. CATERS (Computer Aided Treatment Event Recognition System) was developed to detect treatment events by retrieving and analyzing electronic treatment records. CATERS is designed to make the treatment monitoring process more efficient by automating the search of the electronic record for possible deviations from physician's intention, such as logical inconsistencies as well as aberrant treatment parameters (e.g., beam energy, dose, table position, prescription change, treatment overrides, etc). Over a 5 month period (July 2012-November 2012), physicists were assisted by the CATERS software in conducting normal weekly chart checks with the aims of (a) determining the relative frequency of particular events in the authors' clinic and (b) incorporating these checks into the CATERS. During this study period, 491 patients were treated at the University of Iowa Hospitals and Clinics for a total of 7692 fractions. All treatment records from the 5 month analysis period were evaluated using all the checks incorporated into CATERS after the training period. About 553 events were detected as being exceptions, although none of them had significant dosimetric impact on patient treatments. These events included every known event type that was discovered during the trial period. A frequency analysis of the events showed that the top three types of detected events were couch position override (3.2%), extra cone beam imaging (1.85%), and significant couch position deviation (1.31%). The significant couch deviation is defined as the number of treatments where couch vertical exceeded two times standard deviation of all couch verticals, or couch lateral/longitudinal exceeded three times standard deviation of all couch laterals and longitudinals. On average, the application takes about 1 s per patient when executed on either a desktop computer or a mobile device. CATERS offers an effective tool to detect and report treatment events. Automation and rapid processing enables electronic record interrogation daily, alerting the medical physicist of deviations potentially days prior to performing weekly check. The output of CATERS could also be utilized as an important input to failure mode and effects analysis.


Streptococcal Pharyngitis: Compliance With National Testing Guidelines in a Pediatric Emergency Department.
The Infectious Diseases Society of America (IDSA) guidelines regarding group A streptococcal (GAS) pharyngitis advise against routine testing for patients younger than 3 years, patients without pharyngitis, and patients with symptoms suggesting a viral infection. Group A streptococcal testing may be overused in some clinical settings; thus, we conducted this study to evaluate compliance with the IDSA guidelines in a pediatric emergency department (ED) setting. This retrospective cohort study describes patients younger than 18 years presenting to 2 urban pediatric EDs in 2016 who underwent rapid antigen detection testing for GAS pharyngitis. Testing was classified as noncompliant with the IDSA guidelines if the chief complaint was not indicative of GAS infection and/or the patient age was younger than 3 years. Appropriate nonparametric tests compared groups by IDSA testing compliance status. A total of 13,585 patient encounters met inclusion criteria; 5255 (39%) were noncompliant with the IDSA testing guidelines, the majority due to a chief complaint inconsistent with GAS pharyngitis (67%) and secondarily due to the age of younger than 3 years (48%). Among the patients with noncompliant testing, 51% were prescribed an antibiotic, and return encounters were more likely to occur (13% vs 10%, P < 0.001). Return encounters more commonly resulted in respiratory diagnoses in those with noncompliant GAS testing (60% vs 45%, P < 0.001). Nearly 40% of all pediatric ED encounters with GAS testing were noncompliant with the IDSA guidelines and were associated with greater return encounter rates. Potential negative outcomes from noncompliant GAS testing include misdiagnosis, inappropriate use of antibiotics, allergic reactions, and loss of school days. Informed interventions to reduce unnecessary GAS testing are warranted.


Cryosectioning and Immunostaining of Xenopus Embryonic Tissues.
The Xenopus embryo is a classical vertebrate model for molecular, cellular, and developmental biology. Despite many advantages of this organism, such as large egg size and external development, imaging of early embryonic stages is challenging because of nontransparent cytoplasm. Staining and imaging of thin tissue sections is one way to overcome this limitation. Here we describe a step-by-step protocol that combines cryosectioning of gelatin-embedded embryos with immunostaining and imaging. The purpose of this protocol is to examine various cellular and tissue markers after the manipulation of protein function. This protocol can be performed within a 2-d period and allows detection of many antigens by immunofluorescence.


Multiple primary melanoma in a Thai male: a case report.
Melanoma is a malignant tumor of melanocytes and the most threatening skin cancer documenting one of the highest in mortality rates in comparison to other non-skin cancers due to its potential to metastasize. Although the global incidence of melanoma has increased, the melanoma-related deaths decreased owing to the fact that melanoma is curable under the condition that early diagnosis is made and treatment is undertaken as soon as possible. Patients with primary melanoma developing a second primary melanoma are less common compared to the generalpopulation developing the first. Not only is melanoma less commonly found in Thaipatients but multiple primary melanomas (MPM) are rarely reported. The present report of a 48-year-old Thai male who presented with asymptomatic black patch on the right big toe nail and an atypical mole on the back, both ofwhich were histologically confirmed melanomas. Treatment included amputation of the right big toe and wide excision of melanoma on the back, which cleared the malignancy without recurrence until present. Although MPM are rare in Thais, the authors should be alert in cases displaying multiple moles for the possibility of melanomas. The total body examination, early diagnosis and regular follow-up are important to decrease the mortality rate in melanoma patient.


Correlation of clinical, histological, and cytokeratin profiles of squamous cell carcinoma of the oral tongue with prognosis.
The aim of the present study was to clinically, morphologically, and immunohistochemically correlate the expression of cytokeratins (CKs) 7, 10, 13, 14, 16, and 19 in 30 cases of tongue squamous cell carcinoma (SCC) with disease outcome, metastases, clinical stage (tumor, node, metastasis [TNM]), and histological grade of malignancy proposed by Bryne. Statistical analysis (chi2 test) showed that only histological grading was not significantly correlated with the clinical variables. CK expression varied in the samples analyzed. CK 10 expression was significantly correlated with the presence of metastases, and the expression of CK 16 was related to disease outcome and also to TNM stages III and IV. These results indicate that metastases and TNM are effective prognostic indicators. The histological grading proposed by Bryne did not reflect the biological behavior of the tongue SCC cases studied. Analysis of some intermediate CK filaments can reflect the biological behavior and aggressiveness of some tongue SCCs.


Time-convolutionless master equation for mesoscopic electron-phonon systems.
The time-convolutionless master equation for the electronic populations is derived for a generic electron-phonon Hamiltonian. The equation can be used in the regimes where the golden rule approach is not applicable. The equation is applied to study the electronic relaxation in several models with the finite number of normal modes. For such mesoscopic systems the relaxation behavior differs substantially from the simple exponential relaxation. In particular, the equation shows the appearance of the recurrence phenomena on a time scale determined by the slowest mode of the system. The formal results are quite general and can be used for a wide range of physical systems. Numerical results are presented for a two level system coupled to Ohmic and super-Ohmic baths, as well as for a model of charge-transfer dynamics between semiconducting organic polymers.


5-Fluorouracil combined with the [6S]-stereoisomer of folinic acid in high doses for treatment of patients with advanced colorectal carcinoma. A phase I-II study of two consecutive regimens.
Potentiation of the antitumor activity of 5-fluorouracil (5-FU) by folinic acid has been demonstrated in patients with colorectal adenocarcinoma. Modulation is due to the interaction of thymidylate synthase (TS), fluorodeoxyuridylate (FdUMP), and methylene tetrahydrofolate (5,10-CH2-FH4), which leads to the formation of a stable ternary complex with concomitant enzyme inactivation. Folinic acid consists of a mixture of equal parts of two stereoisomers differing in chirality at the C6 carbon of the pteridine ring. Only the levorotatory [6S]-folinic acid is transformed into active folate cofactors. However, the [6R]-stereoisomer is not inert; it was shown to interfere with the [6S] form at the cellular level. The possibility of a deleterious effect of the unnatural stereoisomer on the modulation of 5-FU led us to carry out 2 consecutive phase I-II studies of 5-FU combined with the [6S]-stereoisomer of folinic acid given in high doses for treatment of patients with advanced colorectal carcinoma. Treatment comprised 5-FU by i.v. infusion for 2 hours (the initial dose was 350 mg/m2/d; it was incremented by 25 mg/m2/d until a maximal dose of 550 mg/m2/d) and [6S]-folinic acid (100 mg/m2/d by rapid i.v. injection in Regimen 1, and 100 mg/m2 by rapid i.v. injection followed by a 2-hour infusion of 250 mg/m2 in Regimen 2) for 5 days, every 21 days. Twenty-five pts and 27 pts were assessed in Regimen 1 and in Regimen 2, respectively. They had had no prior chemotherapy. The median follow-up time was 9 months and 15.5 months for patients treated with Regimen 1 and Regimen 2, respectively. For pts treated with Regimen 1, the response rate was 52% (CR, 12%; PR, 40%). The median time to disease progression was 9.2 months. The probability of survival at 12 months was 73%. For pts treated with Regimen 2, the response rate was 37% (CR, 7%; PR, 30%). The median time to disease progression was 8.9 months. The probability of survival at 12 months was 67%. Improvement in quality of life was achieved in most patients who had symptoms due to the tumor before the start of treatment. The dose-limiting toxic effects (WHO grades > or = 3) were diarrhea, dermatitis, and mucositis. One single episode of grade 4 diarrhea occurred. After injection according to the schema in Regimen 1, [6S]-folinic acid was rapidly cleared from plasma (mean t 1/2 alpha and t 1/2 beta of 7.2 and 126 minutes, respectively). The mean concentration of the [6S]-stereoisomer two hours after injection was 5.8 mmol/L. After a rapid i.v. injection of 100 mg/m2 followed by a 2-hour infusion of 250 mg/m2, the mean concentration of [6S]-folinic acid two hours after the injection was 57.5 mmol/L. Pharmacokinetic data suggests saturation of the metabolic conversion of [6S]-folinic acid when large doses are administered. The [6S]-form of folinic acid potentiates the antitumor effect of 5-FU given concomitantly. However, increase of the daily dose of the folate did not result in a therapeutic improvement. The present results justify a more complete exploration of the pure active stereoisomer as a modulator of the fluoropyrimidines.


A comparison of one- versus two-stage surgery in an experimental model of functional muscle transfer with interposed nerve grafting.
Functional muscle transfer (FMT) combined with cross-facial nerve grafting (CFNG) is the gold standard treatment of chronic unilateral facial palsy, performed by most surgeons over two operative stages to minimise FMT denervation atrophy. Proponents of one-stage surgery cite shorter total recovery time, fewer operative procedures and a possible beneficial neurotrophic effect of muscle attachment. This study aimed to compare one- and two-stage surgery in terms of neural and muscle reinnervation and FMT force production. Forty New Zealand white rabbits underwent one- or two-stage rectus femoris FMT and interposed nerve grafting under different reinnervation conditions. For two-stage surgery, nerve grafting was followed by FMT after three months and by final experiments after a further six months, whereas one-stage groups experienced nerve grafting and FMT together and final experiments after nine months. Outcomes compared were nerve graft and rectus nerve morphometry, FMT reinnervation measured using PGP 9.5, and FMT force production. Statistical analysis was performed by means of the independent samples t-test or the Mann-Whitney Rank Sum test using Statistics Package for the Social Sciences version 11.0.4 for Mac OS X. Nerve graft reinnervation was similar for respective one- and two-stage surgery groups or favoured one-stage surgery. There was no significant difference between respective groups in terms of rectus nerve morphometry, muscle reinnervation, or absolute, weight-adjusted or weight- and control-adjusted tetanic force production. One-stage surgery offers potential advantages including a reduction in the number of surgical procedures, a shorter total recovery time and beneficial economic and healthcare delivery implications. This data supports previous clinical and experimental studies and questions the basis for performing facial reanimation by FMT combined with CFNG over two separate operative stages.


Management of bleeding in the cirrhotic patient.
Important advances have been made in the management of variceal bleeding. Despite these advances, bleeding in the patient with cirrhosis remains one of the most demanding clinical challenges that a gastroenterologist or gastrointestinal surgeon may face. The aim is to identify the source of bleeding, control active bleeding and prevent rebleeding. This requires a multidisciplinary team, and the optimal management algorithm depends on the clinical circumstance of the patient and the local availability of endoscopic, radiological and surgical expertise. Injection sclerotherapy is effective in stopping acute variceal bleeding, but has the drawback of a high incidence of complications. Endoscopic variceal ligation is just as effective, and is associated with fewer complications. An overtube allows repeated introductions of the endoscope to be more tolerable for the patient and protects the airway against aspiration of blood; its use should be encouraged in patients with massive bleeding. Newer ligators can deliver multiple bands without removal of the scope but the high cost of these disposable devices limits their widespread use. Bleeding from gastric varices is even more challenging; the treatment of choice is injection with cyanoacrylate glue. To prevent rebleeding, beta-blockers are recommended for all patients with large varices (including those which have never bled). Injection sclerotherapy or band ligation, conducted at weekly intervals after the initial control of bleeding, is equally effective at obliterating varices and decreasing the risk of further hemorrhage; band ligation results in fewer complications. Other newer treatment modalities for variceal bleeding, such as somatostatin analogs, transjugular intrahepatic portasystemic shunt and liver transplantation, offer more optimal approaches to control bleeding and prevent rebleeding, but may be prohibitively expensive. Even for the most affluent communities, affordability, cost-effectiveness, and resource rationing are important considerations in management of patients with cirrhosis complicated by gastrointestinal bleeding.


Identification of previously unrecognized antiestrogenic chemicals using a novel virtual screening approach.
The physiological roles of estrogen in sexual differentiation and development, female and male reproductive processes, and bone health are complex and diverse. Numerous natural and synthetic chemical compounds, commonly known as endocrine disrupting chemicals (EDCs), have been shown to alter the physiological effects of estrogen in humans and wildlife. As such, these EDCs may cause unanticipated and even undesirable effects. Large-scale in vitro and in vivo screening of chemicals to assess their estrogenic activity would demand a prodigious investment of time, labor, and money and would require animal testing on an unprecedented scale. Approaches in silico are increasingly recognized as playing a vital role in screening and prioritizing chemicals to extend limited resources available for experimental testing. Here, we evaluated a multistep procedure that is suitable for in silico (virtual) screening of large chemical databases to identify compounds exhibiting estrogenic activity. This procedure incorporates Shape Signatures, a novel computational tool that rapidly compares molecules on the basis of similarity in shape, polarity, and other bio-relevant properties. Using 4-hydroxy tamoxifen (4-OH TAM) and diethylstilbestrol (DES) as input queries, we employed this scheme to search a sample database of approximately 200,000 commercially available organic chemicals for matches (hits). Of the eight compounds identified computationally as potentially (anti)estrogenic, biological evaluation confirmed two as heretofore unknown estrogen antagonists. Subsequent radioligand binding assays confirmed that two of these three compounds exhibit antiestrogenic activities comparable to 4-OH TAM. Molecular modeling studies of these ligands docked inside the binding pocket of estrogen receptor alpha (ERalpha) elucidated key ligand-receptor interactions that corroborate these experimental findings. The present study demonstrates the utility of our computational scheme for this and related applications in drug discovery, predictive toxicology, and virtual screening.


Impact of microbial communities from tropical soils on the mobilization of trace metals during dissolution of cinnabar ore.
Biodissolution experiments on cinnabar ore (mercury sulphide and other sulphide minerals, such as pyrite) were performed with microorganisms extracted directly from soil. These experiments were carried out in closed systems under aerobic and anaerobic conditions with 2 different soils sampled in French Guyana. The two main objectives of this study were (1) to quantify the ability of microorganisms to mobilize metals (Fe, Al, Hg) during the dissolution of cinnabar ore, and (2) to identify the links between the type and chemical properties of soils, environmental parameters such as season and the strategies developed by indigenous microorganisms extracted from tropical natural soils to mobilize metals. Results indicate that microbial communities extracted directly from various soils are able to (1) survive in the presence of cinnabar ore, as indicated by consumption of carbon sources and, (2) leach Hg from cinnabar in oxic and anoxic dissolution experiments via the acidification of the medium and the production of low molecular mass organic acids (LMMOAs). The dissolution rate of cinnabar in aerobic conditions with microbial communities ranged from 4.8×10-4 to 2.6×10-3μmol/m2/day and was independent of the metabolites released by the microorganisms. In addition, these results suggest an indirect action by the microorganisms in the cinnabar dissolution. Additionally, because iron is a key element in the dynamics of Hg, microbes were stimulated by the presence of this metal, and microbes released LMMOAs that leached iron from iron-bearing minerals, such as pyrite and oxy-hydroxide of iron, in the mixed cinnabar ore.


Response to anti-IL17 therapy in inflammatory disease is not strongly impacted by genetic background.
Response to the anti-IL17 monoclonal antibody secukinumab is heterogeneous, and not all participants respond to treatment. Understanding whether this heterogeneity is driven by genetic variation is a key aim of pharmacogenetics and could influence precision medicine approaches in inflammatory diseases. Using changes in disease activity scores across 5,218 genotyped individuals from 19 clinical trials across four indications (psoriatic arthritis, psoriasis, ankylosing spondylitis, and rheumatoid arthritis), we tested whether genetics predicted response to secukinumab. We did not find any evidence of association between treatment response and common variants, imputed HLA alleles, polygenic risk scores of disease susceptibility, or cross-disease components of shared genetic risk. This suggests that anti-IL17 therapy is equally effective regardless of an individual's genetic background, a finding that has important implications for future genetic studies of biological therapy response in inflammatory diseases.


Increased Serum 25(OH)D3 Levels in Post-Menopausal Japanese Women with Osteoporosis after 3-Year Bisphosphonate Treatment.
Osteoporosis is characterized by the systemic impairment of bone mass, strength, and microarchitecture, leading to an increased risk of fragility fracture. Bisphosphonates (BPs) are the first-line drugs for osteoporosis. Vitamin D is considered to be essential for osteoporotic treatment. However, long-term effects of BPs on the serum levels of 25-hydroxyvitamin D3 (25(OH)D3) are unknown. Accordingly, in this retrospective study, we collected clinical data of 41 post-menopausal Japanese women with osteoporosis treated with BP for over 3 years, without vitamin D supplementation. We measured lumbar and femoral neck bone mineral density (BMD) and serum levels of bone specific alkaline phosphatase (BAP) as a bone formation marker, and tartrate-resistant acid phosphatase (TRACP)-5b as a bone resorption marker, before and after the 3-year treatment. Serum 25(OH)D3, 1,25(OH)2D3, and whole parathyroid hormone (PTH) were also measured. Notably, no fracture occurred during the treatment. Compared with baseline values, 25(OH)D3 levels were significantly increased from 21.6 to 26.4 ng/mL (P = 0.006), despite no vitamin D supplementation. 1,25(OH)2D3 and whole PTH levels tended to be decreased from 62.6 to 57.8 pg/mL and 27.3 to 25.1 pg/mL, respectively. Both bone formation and resorption markers were significantly suppressed (P < 0.01). Both lumbar BMD (7.3% increase) and femoral neck BMD (4.1% increase) were significantly improved (P < 0.0001) after 3 years of the treatment. Thus, even without vitamin D supplementation, serum 25(OH)D3 levels were significantly increased after 3-year BP therapy. These results suggest that vitamin D supplementation might not be required in the long-term BP therapy for osteoporosis.


Forced oscillation technique: from theory to clinical applications.
The forced oscillation technique (FOT) allows the noninvasive assessment of the mechanical properties of the respiratory system. Given that the technique does not require patient cooperation, it is suitable for the routine evaluation of respiratory function in a variety of clinical applications. In this paper, the rationale and the most conventional equipment and data processing of the technique are described. A number of clinical applications of FOT are briefly reviewed. One common use of the technique is to assess respiratory function in patients with different pathologies and in epidemiology. One of the most referenced applications of FOT is in tests of airway responsiveness to inhaled agents (bronchoprovocation and bronchodilatation). Finally, two recent promising applications of FOT are described: monitoring respiratory resistance during invasive and noninvasive mechanical ventilation, and detection of upper airway obstruction during sleep.


Systems Chronotherapeutics.
Chronotherapeutics aim at treating illnesses according to the endogenous biologic rhythms, which moderate xenobiotic metabolism and cellular drug response. The molecular clocks present in individual cells involve approximately fifteen clock genes interconnected in regulatory feedback loops. They are coordinated by the suprachiasmatic nuclei, a hypothalamic pacemaker, which also adjusts the circadian rhythms to environmental cycles. As a result, many mechanisms of diseases and drug effects are controlled by the circadian timing system. Thus, the tolerability of nearly 500 medications varies by up to fivefold according to circadian scheduling, both in experimental models and/or patients. Moreover, treatment itself disrupted, maintained, or improved the circadian timing system as a function of drug timing. Improved patient outcomes on circadian-based treatments (chronotherapy) have been demonstrated in randomized clinical trials, especially for cancer and inflammatory diseases. However, recent technological advances have highlighted large interpatient differences in circadian functions resulting in significant variability in chronotherapy response. Such findings advocate for the advancement of personalized chronotherapeutics through interdisciplinary systems approaches. Thus, the combination of mathematical, statistical, technological, experimental, and clinical expertise is now shaping the development of dedicated devices and diagnostic and delivery algorithms enabling treatment individualization. In particular, multiscale systems chronopharmacology approaches currently combine mathematical modeling based on cellular and whole-body physiology to preclinical and clinical investigations toward the design of patient-tailored chronotherapies. We review recent systems research works aiming to the individualization of disease treatment, with emphasis on both cancer management and circadian timing system-resetting strategies for improving chronic disease control and patient outcomes.


DIVERGENCE AND GENETIC STRUCTURE IN ADJACENT GRASS POPULATIONS. I. QUANTITATIVE GENETICS.
Additive genetic variances and covariances were estimated for life history and morphological traits in two adjacent populations of the grass, Holcus lanatus L. Significant phenotypic differentiation was found between the two populations for four of the 15 morphological attributes measured. Significant differences in genetic architecture were found between the two populations for 11 of the 13 traits for which genetic variance components could be calculated. Estimates of genetic correlations also showed considerable divergence between the populations. The genetic divergence was much larger than would have been anticipated from simple measures of phenotypic differentiation. These results show that, even in plant species with relatively large population sizes, differences in genetic variance-covariance patterns can occur between adjacent populations.


Requirement for protein synthesis for induction of macrophage tumoricidal activity by IFN-alpha and IFN-beta but not by IFN-gamma.
Peritoneal mouse macrophages elicited by proteose-peptone (pM phi) were treated in vitro with IFN-alpha, IFN-beta, or IFN-gamma in the presence or absence of cycloheximide (Cy), a reversible inhibitor of protein synthesis, and were assayed for cytolytic activity against tumor cells. Inhibition of protein synthesis during treatment of pM phi with IFN-alpha or IFN-beta prevented the development of cytotoxic activity. In contrast, IFN-gamma was fully capable of inducing cytotoxic pM phi in the presence of Cy. Moreover, pM phi treated with mixtures of IFN in the presence of Cy were activated for cytotoxicity only by IFN-gamma together with IFN-alpha or IFN-beta, but not by IFN-alpha plus IFN-beta. These results indicate that the activation of pM phi by IFN-gamma is independent of new protein synthesis, whereas the activation of pM phi by IFN-alpha and/or IFN-beta requires active protein synthesis, suggesting that the mechanism of induction of cytotoxic pM phi by IFN-gamma differs from that by the other types of IFN.


[Uptake behavior of bone metastases of hypernephroma in the 99m Tc-MDP bone scintigram. A comparison with x-ray findings].
Ninety-one radiologically confirmed osteolytic metastases in 30 patients with hypernephromas were studied with regard to their uptake of 99mTc-MDP and this was compared with the radiological findings. In 16% of the radiologically proven metastases, there was no correlation with their isotope uptake. Compared with other bone metastases whose isotope uptake has been studied and described in the literature, there appears to be a higher proportion of hypernephroma secondaries that do not show uptake of 99mTc-MDP.


Fragment-Based NMR Screening of the BPTF PHD Finger Methyl Lysine Reader Leads to the First Small-Molecule Inhibitors.
Methyl lysine readers, specifically PHD fingers, are emerging epigenetic targets in human diseases. For example, several PHD finger fusions are implicated in clinical cases of acute myeloid leukemia, highlighting the potential for PHD inhibitors in disease regulation. However, limited chemical matter targeting PHD fingers exists. Here we report the first fragment-based screen against the BPTF PHD to identify several of the first reported BPTF PHD-targeting small-molecule ligands. We used ligand-observed NMR to first screen a fragment library, followed by biophysical validation to prioritize two scaffolds, pyrrolidine- and pyridazine-containing fragments. Structural predictions show that these respective scaffolds may engage two distinct subpockets on the protein. The demonstrated ligandability of the BPTF PHD supports the future development of methyl lysine reader chemical probes to study their oncogenic functions.


[Results of skin prick tests and evaluation of serum antigen specific immunoglobulin E in patients with atopic dermatitis and airborne allergy with regards to the type of sensitising allergens and seasonal course of the disease].
Atopic dermatitis (AD) is a chronic inflammatory skin disease associated with sensitivity to common airborne allergens. The aim of the study was to evaluate immediate type of immunological reaction initiated by main types of airborne allergens in the pathomechanism of atopic dermatitis. The exacerbation of skin inflammation of patients with AD in relation to the seasons was also evaluated. 529 patients with AD aged (0.5-60 years) who fulfilled basic Hanifin and Rajka criteria and 60 healthy volunteers in the control group were investigated. In order to evaluate IgE-mediated allergy to common airborne allergens skin prick tests (SPT) were performed (26 airborne allergens) and concentration of serum antigen specific IgE (asIgE) was measured. Evaluation of exacerbation of skin inflammation of patient with AD in for patient with monovalent allergy of airborne allergens. Our results indicated predominance of grass pollen (63.2%) and house dust mite (57.0%) allergens of all patients sensitive to airborne allergens (n-405). In the group of patients sensitive to pollen allergens seasonal exacerbation of skin inflammation was predominant (over 90% of patients) and in the groups of patients sensitive to house dust mite and animal allergens the clinical manifestation of allergy for the whole year was observed in the most patients (77.1% and 57.1%). We conclude, that house dust mite and plant pollen allergens play an important role in the pathomechanism of atopic dermatitis.


The release of prostaglandin-like substances during platelet aggregation and pulmonary microembolism.
During pulmonary microembolism subsequent to induced platelet aggregation in vivo, a pressor response is elicited in the lungs due to the release of vasoactive substances. During the prefusion of isolated cat lungs with whole blood, platelet aggregation induced by collagen released prostaglandin-like substances (PG-LS), and a rabbit aorta contracting substance (RCS) as measured by continuous biosassay of the venous effluent. This release occurred in parallel to the pulmonary pressor response. The same amount of PG-LS and RCS was released when the lungs were replaced by a blood filter to trap platelet aggregates. Apparently PG-LS and RCS are released from platelets during their aggregation. As E- and F-type PGs are rapidaly inactivated in the pulmonary circulation, there must either be an equal generation of PGs in the lungs themselves, or rather, the release of PGs from platelets must occur distal to the inactivation mechanism without any additional PG-release from the lungs. The exact role of PGs in the lung responses to intravascular platelet aggregation is not clear.


Development of a canine model for recurrent laryngeal injury by harmonic scalpel.
Various energy devices had been used in thyroid surgery. Aim of study is to develop canine model for recurrent laryngeal nerve injury by harmonic scalpel and to evaluate feasibility of using this model for evaluating the safety use of harmonic scalpel during thyroid surgery. Nine dogs were divided into 3 groups according to distance between harmonic scalpel application and recurrent laryngeal nerve; group 1 (1 mm), 2 (2 mm), and 3 (3 mm). Vocal cord function was assessed pre- and postoperatively using video laryngoscopy. Harmonic scalpel was applied adjacent to left recurrent laryngeal nerve and, two weeks later, right recurrent laryngeal nerve at assigned distances. Recurrent laryngeal nerves were evaluated for subacute and acute morphologic changes. Laryngoscopy demonstrated 3 abnormal vocal cords in group 1, 1 in group 2, and no in group 3 (P=0.020). Subacute histologic changes were observed in nerves with abnormal function. Acute histologic changes were observed 5/8 (62.5%) in group 1, 1/7 (14.3%) in group 2, and not in group 3. We developed canine model for recurrent laryngeal injury. The functional outcomes matched with the histologic changes. These warrant further study to determine the safety margin for energy device in vicinity of recurrent laryngeal nerve.


[An Elderly Patient with Non-Small Cell Lung Cancer Who Responded to Salvage S-1 Monotherapy after Gefitinib Therapy].
S-1 is one of the effective chemotherapy regimens for treating non-small cell lung cancer. We report of an elderly patient with non-small cell lung cancer who responded to S-1 monotherapy following gefitinib therapy. An 83-year-old woman was diagnosed with advanced adenocarcinoma of the lungs (cT3N3M1a, Stage IV). Considering her age, monotherapy with vinorelbine was administered as first-line chemotherapy. Despite the completion of four courses, she was diagnosed with progressive disease. Thereafter, after considering her status as a non-smoking woman, gefitinib was introduced as second-line chemotherapy, which resulted in significant tumor size reduction.Tumor regrowth was identified 16 months later, and gefitinib was switched to erlotinib, but the tumor kept increasing in size.S -1 monotherapy was introduced as fourth-line chemotherapy, and the tumor began to decrease in size again. A partial response was obtained after 10 months, without serious adverse effects. Gefitinib following S-1 monotherapy resulted in long-term tumor size control for a total of 27 months in an elderly patient with advanced non-small cell lung cancer.S -1 monotherapy might be one of the options for salvage therapy after gefitinib treatment becomes ineffective.


Modified Alendronate Mitigates Mechanical Degradation of the Rotator Cuff in an Osteoporotic Ovine Model.
Osteoporosis is an independent risk factor for failure after arthroscopic rotator cuff repair. Since rerupture rates after rotator cuff repair are associated with decreased bone mineral density and bone microarchitecture, adaptations of biomechanical properties of the rotator cuff enthesis in patients with osteoporosis remain unclear. Additionally, the effects of osteogenic therapy carrier drugs used for the treatment of osteoporosis on rotator cuff structure and properties have not been previously documented. To investigate the changes to soft tissue biomechanics and insertional structure secondary to osteoporosis with and without an osteogenic therapy carrier (ie, modified alendronate). Controlled laboratory study. Biomechanical, histopathological, and microcomputed tomography analyses were performed on 20 shoulders obtained from 10 osteoporotic sheep randomly allocated to modified bisphosphonate (ie, alendronate) or control (ie, osteoporotic without treatment) groups; 6 shoulders from healthy sheep were utilized for comparison purposes. Tendons from the control group exhibited a 57% decrease in undeformed Young modulus as compared with the healthy group (P = .010). Tendons from the modified bisphosphonate treatment group exhibited a 229% increase in initial Young modulus as compared with the control group (P = .010). Marked changes within the tendon insertional organization were noted in both the control and the modified bisphosphonate treatment group samples as evidenced by increased interdigitation of the bone-mineralized fibrocartilaginous junction. The control samples exhibited a markedly paucicellular insertion, whereas the modified bisphosphonate treated tendons exhibited a hypercellular insertional region as compared with the healthy group. Both groups exhibited significantly (P < .01) decreased bone quality underlying the infraspinatus insertion, as evidenced by all microcomputed tomography outcome parameters. This work illuminates changes to rotator cuff tendon secondary to osteoporosis. Specifically, it revealed decreased tendon modulus and altered insertional structure in the osteoporotic samples. Secondarily, these data revealed increases in tendon modulus accompanied by increased cellularity within the tendon insertion region after systemic modified bisphosphonate injections. Bisphosphonate treatment may have a positive effect on the healing of the enthesis after rotator cuff repair.


An imaginary legal conundrum: A reply to the response by Mahomed, Nöthling-Slabbert and Pepper.
In their original article on the subject of research using human biological material, Mahomed, Nöthling-Slabbert and Pepper advanced the notion that the law regarding ownership of human biological material is uncertain, and proposed that our country's healthcare policy of altruism be changed to mandatory profit-sharing by research participants. In my critique article, I took issue with the notion that the relevant law is uncertain, and suggested that Mahomed et al. failed to present a convincing argument in support of the proposed policy change from altruism to profit-sharing. In their response to my critique article, Mahomed et al. persist with the notion that the relevant law is uncertain; I suggest that this notion is erroneous, as our common law in this regard is well established, and as the authors base their argument exclusively on foreign case law. The authors further fail to make use of the opportunity to augment their argument in support of their proposed policy change from altruism to profit-sharing - in fact, they contradict themselves by disavowing their proposed policy change.


Submillimeter fMRI reveals a layout of dorsal visual cortex in macaques, remarkably similar to New World monkeys.
The macaque dorsal occipital cortex is generally thought to contain an elongated third visual area, V3d, extending along most of the rostral border of area V2. In contrast, our submillimeter retinotopic fMRI maps (0.6-mm isotropic voxels, achieved by implanted phased-array receive coils) consistently show three sectors anterior to V2d. The dorsal (mirror image) sector complies with the traditional V3d definition, and the middle (nonmirror image) sector with V3A. The ventral (mirror image) sector bends away from V2d, as does the ventrolateral posterior area (VLP) in marmosets and the dorsolateral posterior area (DLP) in owl monkeys, and represents the entire contralateral hemifield as V3A does. Its population-receptive field size, however, suggests that this ventral sector is another area at the same hierarchical level as V4d. Hence, contrary to prevailing views, the retinotopic organization of cortex rostral to V2d differs substantially from widely accepted models. Instead, it is evolutionarily largely conserved in Old and New World monkeys given its surprisingly similar overall visuotopic organization.


Venovenous Extracorporeal Membrane Oxygenation to Facilitate Removal of Endobronchial Tumors.
Short-term extracorporeal membrane oxygenation is a useful adjunct to thoracic procedures. We report the cases of 2 middle-aged men who were supported with venovenous extracorporeal membrane oxygenation to facilitate tumor debulking and recanalization of the carina and mainstem bronchi. Neither patient had major complications or adverse events. These cases suggest that short-term extracorporeal membrane oxygenation is safe in patients undergoing complex resection or debulking of endobronchial lesions.


Nuclear receptors in pancreatic tumor cells.
This review focuses on nuclear receptors expressed in pancreatic cancer. An extensive search of articles published up to March 2013 was conducted using the MEDLINE database. The key words used were "pancreatic cancer", "molecular receptors" and "growth factors". A total of 112 articles referred to pancreatic cancer, molecular receptors and/or growth factors were included. Receptors of growth factors, such as the epithelial growth factor receptor, insulin-like growth factor-1 receptor, vascular endothelial growth factor receptor and others, such as integrin α5β1, somatostatin receptors, the death receptor 5, claudin, notch receptors, mesothelin receptors, follicle-stimulating hormone receptors, the MUC1 receptor, the adrenomedullin receptor, the farnesoid X receptor, the transferrin receptor, sigma-2 receptors, the chemokine receptor CXCR4, the urokinase plasminogen activator receptor, the ephrine A2 receptor, the GRIA3 receptor, the RON receptor and the angiotensin II receptor AT-1 are expressed in pancreatic tumor cells. These molecules are implicated in tumor growth, apoptosis, angiogenesis, metastasis etc. After identifying the molecular receptors associated with the pancreatic cancer, many more target molecules playing important roles in tumor pathophysiology and senescence-associated signal transduction in cancer cells will be identified. This may have a significant influence on diagnosis, therapy and prognosis of pancreatic cancer.


Lithium Intercalation into the Excitonic Insulator Candidate Ta2NiSe5.
A new reduced phase derived from the excitonic insulator candidate Ta2NiSe5 has been synthesized via the intercalation of lithium. LiTa2NiSe5 crystallizes in the orthorhombic space group Pmnb (no. 62) with lattice parameters a = 3.50247(3) Å, b = 13.4053(4) Å, c = 15.7396(2) Å, and Z = 4, with an increase of the unit cell volume by 5.44(1)% compared with Ta2NiSe5. Significant rearrangement of the Ta-Ni-Se layers is observed, in particular a very significant relative displacement of the layers compared to the parent phase, similar to that which occurs under hydrostatic pressure. Neutron powder diffraction experiments and computational analysis confirm that Li occupies a distorted triangular prismatic site formed by Se atoms of adjacent Ta2NiSe5 layers with an average Li-Se bond length of 2.724(2) Å. Li-NMR experiments show a single Li environment at ambient temperature. Intercalation suppresses the distortion to monoclinic symmetry that occurs in Ta2NiSe5 at 328 K and that is believed to be driven by the formation of an excitonic insulating state. Magnetometry data show that the reduced phase has a smaller net diamagnetic susceptibility than Ta2NiSe5 due to the enhancement of the temperature-independent Pauli paramagnetism caused by the increased density of states at the Fermi level evident also from the calculations, consistent with the injection of electrons during intercalation and formation of a metallic phase.


Evaluation of the antifungal effects of mineral trioxide aggregate materials.
The aim of this study was to evaluate and compare the antifungal effect of white-coloured mineral trioxide aggregate (WMTA) and grey mineral trioxide aggregate (GMTA) using a tube-dilution test. MTA preparations were freshly mixed and tested after 24 h on Candida albicans. The experiment was carried out in 24-well culture plates. Fifty wells were used and divided into four experimental groups (freshly mixed WMTA, freshly mixed GMTA, 24 h-set WMTA and 24 h-set GMTA) of 10 wells each and control groups of five wells each. Plates of Sabouraud dextrose agar mixed with C. albicans served as positive control, and Sabouraud dextrose agar without C. albicans served as negative control. Fresh inoculate of C. albicans was prepared by growing an overnight culture from a stock culture. Aliquots of C. albicans were then taken from the stock culture and plated on the agar compound of the experimental and control groups. All plates were incubated at 37 degrees C for 1, 24 and 72 h. Growth of fungi was monitored daily by the presence of turbidity. Results showed that in the freshly mixed as well as 24 h-set MTA cements fungal growth was observed during 1-h incubation, whereas by increasing the incubation time, no fungal growth was observed in 24 and 72 h. It was concluded that MTA cements (freshly mixed and 24-h set) were effective against C. albicans.


Microscopic dynamics of the orientation of a hydrated nanoparticle in an electric field.
We use atomistic simulations to study the orientational dynamics of a nonpolar nanoparticle suspended in water and subject to an electric field. Because of the molecular-level effects we describe, the torque exerted on the nanoparticle exceeds continuum-electrostatics-based estimates by about a factor of 2. The reorientation time of a 16.2 x 16.2 x 3.35 A(3) nanoparticle in a field |E| > 0.015 V/A is an order of magnitude less than the field-free orientational time (approximately 1 ns). Surprisingly, the alignment speed is nearly independent of the nanoparticle size in this regime. These findings are relevant for design of novel nanostructures and sensors and development of nanoengineering methods.


Colonic cytomegalovirus DNA detection by polymerase chain reaction does not influence outcomes in inflammatory bowel disease and immunosuppressed cohorts.
Cytomegalovirus (CMV) colitis is associated with negative outcomes in inflammatory bowel disease (IBD) and immunosuppressed cohorts and therefore requires timely recognition for appropriate management. We aimed to evaluate the diagnostic tools for CMV colitis and their associations with clinical outcomes. A retrospective cohort study of patients in a metropolitan health service with colonic samples analysed for CMV between 2012 and 2022, stratified into IBD and non-IBD groups, was performed. The main outcome measures were the prevalence of positive and negative results for each CMV test, as well as need for colectomy, use of antiviral and hospital length of stay. Five hundred eighty-two biopsies from 418 patients were included; the median age was 36 years (interquartile range, 24-52 years) and 223 (53.3%) were men. Four hundred sixty-one (79.2%) biopsies were from patients with IBD and 121 (20.8%) were from those without IBD. There were similar proportions of positive CMV histology (IBD 5.9% and non-IBD 7.4%) and tissue CMV polymerase chain reaction (PCR) in the two groups (IBD 5.6% and non-IBD 5.0%), but within each group, results were discordant. Positive CMV histology was significantly associated with need for colectomy in the IBD group, while positive tissue CMV PCR was not. Positive CMV histology, and tissue and serum CMV PCR were all significantly associated with antiviral use. Positive serum CMV PCR was significantly associated with colectomy. Histopathology remains the most predictive tool in assessing CMV colitis, while qualitative tissue CMV PCR was found to have limited utility. Quantitative serum CMV PCR may be useful but requires further evaluation.


Transanal Minimally Invasive Surgery.
Transanal minimally invasive surgery (TAMIS) was first described in 2010 as a crossover between single-incision laparoscopic surgery and transanal endoscopic microsurgery (TEM) to allow access to the proximal and mid-rectum for resection of benign and early-stage malignant rectal lesions. The TAMIS technique can also be used for noncurative intent surgery of more advanced lesions in patients who are not candidates for radical surgery. Proper workup and staging should be done before surgical decision-making. In addition to the TAMIS port, instrumentation and set up include readily available equipment found in most operating suites. TAMIS has proven its usefulness in a wide range of applications outside of local excision, including repair of rectourethral fistula, removal of rectal foreign body, control of rectal hemorrhage, and as an adjunct in total mesorectal excision for rectal cancer. TAMIS is an easily accessible, technically feasible, and cost-effective alternative to TEM.


Control of interchain contacts, solid-state fluorescence quantum yield, and charge transport of cationic conjugated polyelectrolytes by choice of anion.
Simple procedures are provided for exchanging charge-compensating ions in conjugated polyelectrolytes by progressive dilution of the original species and for determining the degree of ion exchange by using X-ray photoelectron spectroscopy. By using these methods, the bromide ions in poly[(9,9-bis(6'-N,N,N-trimethylammoniumbromide)hexyl)fluorene-co-alt-4,7-(2,1,3-benzothiadiazole)]were exchanged with BF4-, CF3SO3-, PF6-, BPh4-, and B(3,5-(CF3)2C6H3)4- (BArF4-). Absorption, photoluminescence (PL), and PL quantum yields (Phi) were measured in different solvents and in solid films cast from methanol. Examination of the resulting trends, together with the spectral bandshapes in different solvents, suggests that increasing the counteranion (CA) size decreases interchain contacts and aggregation and leads to a substantial increase of Phi in the bulk. Size analysis of polymers containing Br- and BArF4- in water by dynamic light scattering techniques indicates suppression of aggregation by BArF4-. Nanoscale current-voltage measurements of films using conducting atomic force microscopy show that hole mobilities and, more significantly, charge injection barriers are CA dependent. These results show that it is possible to significantly modify the optoelectronic properties of conjugated polyelectrolytes by choosing different counterions. A parent conjugated backbone can thus be fine-tuned for specific applications.


Dental implant retrieval analyses.
The evolution of surgical implant devices has been dependent upon a multidisciplinary coordination between the basic and applied biological and physical sciences. In this regard, engineering failure analyses of retrieved prostheses represent a significant contribution. Dental implant retrieval studies have provided guidance for biomaterials, designs and biomechanical function, specialized surface treatments for controlling tissue responses, and associated surgical, periodontal, and restorative regimes. The recent expansion of design concepts and restorative procedures places a new emphasis on the need for interrelated prospective laboratory, laboratory animal, and human device investigations. Retrospective retrieval analyses continue to provide guidance with regard to key concept development and the formulation of important questions and hypotheses for future investigations.


Biomimetic hydroxyapatite used in the treatment of periodontal intrabony pockets: clinical and radiological analysis.
Hydroxyapatite (PA) has a chemical composition and physical structure very similar to natural bone and therefore it has been considered to be the ideal biomaterial able to ensure a biomimetic scaffold to use in bone tissue engineering. The aim of this study is to clinically test hydroxyapatite used as osteoconductive biomaterial in the treatment of periodontal bone defects. Clinical and radiological evaluations were conducted at 6, 12 and 18 months after the surgery. Forty patients with 2- and 3-wall intrabony pockets were enrolled in this study. PPD, CAL, radiographic depth (RD) and angular defects were preoperatively measured. After surgery, patients were re-evaluated every 6 months for 18 months. Statistical analyses were also performed to investigate any differences between preoperative and postoperative measurements. Paired t-test samples conducted on the data obtained at baseline and 18 months after, showed significant (p<0.01) differences in each measurement performed. The role of preoperative RD was demonstrated to be a significant key factor (p<0.01). A relevant correlation between preoperative PPD and CAL gain was also found. Within the limitations of this study, the absence of anatomical variables, except the morphology of the bone defect, emphasizes the importance of the proper surgical approach and the graft material used.


Expression and localization of androgen receptor-interacting protein-4 in the testis.
Androgen receptor-interacting protein 4 (ARIP4) belongs to the SNF2 family of proteins involved in chromatin remodeling, DNA excision repair, and homologous recombination. It is a DNA-dependent ATPase, binds to DNA and mononucleosomes, and interacts with androgen receptor (AR) and modulates AR-dependent transactivation. We have examined in this study the expression and cellular localization of ARIP4 during postnatal development of mouse testis. ARIP4 was detected by immunohistochemistry in Sertoli cell nuclei at all ages studied, starting on day 5, and exhibited the highest expression level in adult mice. At the onset of spermatogenesis, ARIP4 expression became evident in spermatogonia, pachytene, and diplotene spermatocytes. Immunoreactive ARIP4 antigen was present in Leydig cell nuclei. In Sertoli cells ARIP4 was expressed in a stage-dependent manner, with high expression levels at stages II-VI and VII-VIII. ARIP4 expression patterns did not differ significantly in testes of wild-type, follicle-stimulating hormone receptor knockout, and luteinizing hormone receptor knockout mice. In testes of hypogonadal mice, ARIP4 was found mainly in interstitial cells and exhibited lower expression in Sertoli and germ cells. In vitro stimulation of rat seminiferous tubule segments with testosterone, FSH, or forskolin did not significantly change stage-specific levels of ARIP4 mRNA. Heterozygous ARIP4(+/-) mice were haploinsufficient and had reduced levels of Sertoli-cell specific androgen-regulated Rhox5 (also called Pem) mRNA. Collectively, ARIP4 is an AR coregulator in Sertoli cells in vivo, but the expression in the germ cells implies that it has also AR-independent functions in spermatogenesis.


Quantification of Structural Defects Using Pixel Level Spatial Information from Photogrammetry.
Aging infrastructure has drawn increased attention globally, as its collapse would be destructive economically and socially. Precise quantification of minor defects is essential for identifying issues before structural failure occurs. Most studies measured the dimension of defects at image level, ignoring the third-dimensional information available from close-range photogrammetry. This paper aims to develop an efficient approach to accurately detecting and quantifying minor defects on complicated infrastructures. Pixel sizes of inspection images are estimated using spatial information generated from three-dimensional (3D) point cloud reconstruction. The key contribution of this research is to obtain the actual pixel size within the grided small sections by relating spatial information. To automate the process, deep learning technology is applied to detect and highlight the cracked area at the pixel level. The adopted convolutional neural network (CNN) achieves an F1 score of 0.613 for minor crack extraction. After that, the actual crack dimension can be derived by multiplying the pixel number with the pixel size. Compared with the traditional approach, defects distributed on a complex structure can be estimated with the proposed approach. A pilot case study was conducted on a concrete footpath with cracks distributed on a selected 1500 mm × 1500 mm concrete road section. Overall, 10 out of 88 images are selected for validation; average errors ranging from 0.26 mm to 0.71 mm were achieved for minor cracks under 5 mm, which demonstrates a promising result of the proposed study.


Biomechanical Role of Trabecular Microstructure on Peri-implant Strain Based on Micro-CT Finite Element Modeling of Aging Mice.
To evaluate the influence of age and trabecular microstructure on peri-implant strain in aging and young mice models under compressive load. Eighteen 4-week-old female C57BL/6 mice (n = 6) were subjected to a 1.2% calcium content diet (young normal calcium group), and 7-month-old mice (n = 12) were randomly subjected to 0.01% and 1.2% calcium content diets (aging low and normal calcium groups, respectively) for 3 weeks. Histomorphometric and microcomputed tomography (micro-CT) analyses were used to investigate local alveolar bone microstructure. One maxilla segment from each group was reconstructed using micro-CT images to highlight the trabecular microstructure. A finite element analysis based on a computational model of the maxilla segment was performed to investigate peri-implant strain. Implants with three different diameters (0.3, 0.4, and 0.5 mm) were analyzed in these models. The aging low calcium group showed worse cancellous microstructure in hematoxylin and eosin (HE) staining, significantly increased osteoclast numbers (P < .05), and reduced bone volume fraction and trabecular thickness compared with the aging normal calcium group (P < .05). However, the young normal calcium group presented no difference in trabecular microstructure and osteoclast numbers compared with the aging normal calcium group. The aging low calcium group demonstrated increased strain intensity compared with the aging normal calcium group, whereas the young normal calcium and aging normal calcium groups showed comparable strain magnitude. The strain intensity of peri-implant bone increased with worse cancellous microstructure. When the diameter increased from 0.3 mm to 0.4 mm, the percentages of pathologic overload decreased regardless of bone microstructure. Deteriorated bone microstructure induced by a low calcium diet determined higher strain intensity, whereas, whenever age had no significant effect on trabecular microstructure, consequently, there was no substantial influence on strain. An increase of implant diameters can improve the strain distribution. Clinical decision-making should take into consideration the patient-specific and site-specific trabecular microstructure in preoperative assessment.


Selective ligation of uterine artery branches accelerates fetal growth in the rat.
We determined if reducing litter number by selective fetal ablation (A) might enhance the growth of the surviving fetuses. On day 14 of the rat's 21.5-day gestation, we ligated branches of the uterine artery at their secondary division. Each of these branches supplies a placenta and its fetus, and ligation kills them. Every other fetus in litters of eight to 14 fetuses was ablated. Each A maternal rat was matched to a control with an equal number of fetuses. Ablation reduced fetal number (from 8-14 to 4-7) and increased fetal growth (birth weight 5.84 +/- 0.05 versus 5.20 +/- 0.05 g, p less than 0.001). In the A but not control litters, newborn body mass was negatively related to litter number. Fetuses of A litters had increased carcass, liver, and brain mass. On days 18 and 19, fetal plasma glucose concentrations, fetal/maternal glucose ratios, insulin concentrations, and hepatic glycogen concentrations were increased suggesting that A increases glucose provision to the surviving fetuses. Although these observations imply that A enhances glucose provision resulting in stimulated growth of insulin-sensitive tissues, the growth of the brain, purportedly a tissue not sensitive to insulin, was also increased. In addition, the growth rate of A fetuses continued to be increased on days 20 and 21 despite normal fetal plasma glucose and insulin. These observations indicate that with A, factors other than insulin also stimulated growth. Of note, newborn A pups developed hypoglycemia at 20 and 60 min as a result of increased insulin secretion.


High BRAF mutation frequency does not characterize all melanocytic tumor types.
Cutaneous melanoma (CM) is the most lethal form of skin cancer. Along with some benign melanocytic tumors, the majority shows BRAF or NRAS mutation, but it is not known whether these are essential to all forms of melanocytic neoplasia. We screened 79 melanocytic tumors of different types for BRAF and NRAS mutations and looked at MAPK pathway activity using immunohistochemistry in a subset. Significant differences in BRAF exon 15 mutation frequency were found: 14/16 (87.5%) in common acquired naevi (CANs), 9/12 (75%) in CMs, 0/26 in Spitz naevi and 3/25 (12%) in blue naevi (p < 0.01). We looked at whether Spitz and blue naevi showed a compensatory increase in BRAF exon 11 and/or NRAS exons 1 and 2 mutations to account for the low BRAF exon 15 mutation frequency. NRAS mutations were found in only 1/16 (6.3%) Spitz naevi and 0/15 blue naevi. In addition, NRAS mutations were found in 2/11 (18.2%) CANs and 3/12 (25%) CMs. None of the tumors showed BRAF exon 11 mutations. Despite their low combined BRAF and NRAS mutation frequency, Spitz naevi showed strong MAPK pathway activation as measured by cytoplasmic expression of dually phosphorylated ERK1/2, while blue naevi had weak pathway activation. We conclude that BRAF and NRAS mutations are not necessary for melanocytic tumor development and that some types of tumor must arise by alternative mechanisms.


Utility of immunohistochemical expression of E-cadherin in colorectal carcinoma.
Reduced expression of E-cadherin, an intercellular junction protein, is associated with differentiation and metastasis of multiple cancers, including colorectal cancer. To investigate the utility of the immunohistochemistry of E-cadherin as a prognostic marker for colorectal cancer (CRC). Immunohistochemical analysis for E-cadherin was performed on 100 paraffin blocks retrieved from resected specimens of CRC patients. The collected data were statistically analysed. Among the 100 patients, men comprised 58% and the majority had tumour size of 5-10 cm (55%). Grade II CRC was more common (74%) than grade I and III (13% each). The correlation of E-cadherin expression with lymph node involvement was statistically significant, as revealed by p-value < 0.01, with about 27% in N1 and 13% in N2 stage. E-cadherin expression was significantly correlated with tumour differentiation pattern (p < 0.01), wherein out of 13 poorly differentiated carcinomas, 38.5% and 30.5% of samples showed negative and weak E-cadherin staining, respectively. Furthermore, a shift from membranous E-cadherin staining in normal cells to cytoplasmic and mixed staining was observed in cancer cells. The study indicates that immunohistochemical E-cadherin expression has prognostic value, as revealed by its loss of expression in poorly differentiated cells and lymph node metastasis.


The impact of residency training in family medicine on hospital admissions due to Ambulatory-care Sensitive Conditions in Rio de Janeiro.
Lack of skilled human resources in primary care remains a major concern for policymakers in low- and middle-income countries. There is little evidence supporting the impact of residency training in family medicine in the quality of care, and it perpetuates misconceptions among policymakers that the provision of primary care can be easily done by any physician without special training. This article compares the risk of patients being hospitalized due to Ambulatory care sensitive conditions and the odds of having follow-up visits in primary care after hospital discharge, according to the type of their medical provider: (1) Generalists (reference), (2) Family physicians; and, (3) patients with no consultations prior to the event. Multilevel multivariate binomial regression models estimated the relative risks of a patient being hospitalized in a given month and the relative risks for the occurrence of a follow-up visit in primary care in a retrospective cohort of 636.640 patients between January 2013 and July 2018 in Rio de Janeiro. For all 14 conditions, there was a higher risk of hospitalization when patients had no consultation in primary care prior to the event. Except for Ear, Nose and Throat infections, patients seen by family physicians had a lower risk of being hospitalized, compared to patients seen by Generalists. Follow-up visits were more likely to happen among patients treated by family physicians for almost every condition analyzed. With two years of training in family medicine, Family physicians can reduce the risk of their patients being hospitalized and increase the likelihood of those patients having a follow-up consultation in primary care. Investments in residency training in family medicine should be made to fix the shortage of skilled physicians in primary care, reduce hospitalizations and improve quality and continuity of care.


Concomitant acute stroke, pulmonary and myocardial infarction due to in-transient thrombus across a patent foramen ovale
Non-atherosclerotic myocardial infarction (MI) is an important but often misdiagnosed cause of acute MI. Furthermore, non-atherosclerotic MI with concomitant acute stroke and pulmonary embolism due to in-transit thrombus across a patent foramen ovale (PFO) is a rare but potentially fatal combination (1, 2, 3). Early detection of this clinical entity can facilitate delivery of targeted therapies and avoid poor outcome (1, 2). Here, we describe a 68-year-old female with hypertension, tobacco abuse and chronic obstructive pulmonary disease presenting with facial droop, right arm weakness and aphasia. Head computed tomography (CT) without contrast was unremarkable. ECG showed an acute inferolateral ST-elevation MI (Fig. 1, Panel A). As patient presented with both an acute neurological deficit and MI, clinical suspicion of non-atherosclerotic MI was raised and the patient underwent concurrent emergency coronary angiography (CAG) and transesophageal echocardiogram (TEE). TEE revealed highly mobile masses in the left and right atrium (Fig. 1, Panel B and Video 1). The large mass (thrombus or cast of a deep venous thrombus) was caught in a PFO (Fig. 1, Panel C, D, E and Videos 2, 3). A second smaller mass/thrombus was seen on the Eustachian valve near the right atrial/inferior vena cava junction (Fig. 1, Panel F and Video 4). CAG confirmed a 100% occluded distal right posterolateral artery suggestive of an embolic phenomenon. The patient underwent successful thrombectomy, retrieving a large thrombus burden (Fig. 1, Panel G and Videos 5, 6, 7). CT angiography showed occluded internal carotid artery (Fig. 1, Panel H). Pathology from thrombectomy confirmed fibrin-rich thrombus. The patient had bilateral lower extremity deep vein thrombosis and bilateral diffuse pulmonary embolisms.


Advanced glycation end products affect cholesterol homeostasis by impairing ABCA1 expression on macrophages.
Reverse cholesterol transport (RCT), which is intimately linked to high-density lipoproteins (HDLs), plays a key role in cholesterol homeostasis and the prevention of atherosclerosis. The goal of the present study was to investigate the effect of aging and advanced glycation end products (AGEs) on RCT as well as on other factors that may affect the antiatherogenic property of HDLs. The transfer of macrophage-derived cholesterol to the plasma and liver and then to the feces for elimination was significantly lower in aged mice than in young mice. Chronic injection of d -galactose (D-gal) or AGEs also significantly reduced RCT (65.3% reduction in [3H]cholesterol levels in the plasma of D-gal-treated mice after 48 h compared with control mice, P < 0.01). The injection of both D-gal and aminoguanidine hydrochloride increased [3H]cholesterol levels in the plasma, although the levels were lower than those of control mice. The in vitro incubation of HDLs with dicarbonyl compounds increased the carbonyl and conjugated diene content of HDLs and significantly reduced PON1 paraoxonase activity (87.4% lower than control HDLs, P < 0.0001). Treating J774A.1 macrophages with glycated fetal bovine serum increased carbonyl formation (39.5% increase, P < 0.003) and reduced ABCA1 protein expression and the capacity of macrophages to liberate cholesterol (69.1% decrease, P < 0.0001). Our results showed, for the first time, that RCT is altered with aging and that AGEs contribute significantly to this alteration.


Dentists' perception of their treatment practices versus documented evidence.
To compare the quality of real-life treatment practices to dentists' perceptions of treatment rendered. One administrative unit of the Finnish public oral health service. The original oral health records of a randomly selected sample of young adults who received treatment during 1994-1996 provided data on actual clinical examinations (n=208), radiographs (n=312), and root canal treatment courses (n=148) carried out by 50 dentists. Dentists' perceptions of the treatment rendered were obtained through a structured questionnaire completed during their working hours in 1996. Criteria for assessing the quality of treatment practices were based on Finnish health legislation, authoritative instructions, and consensus reports. Based on responses, 77% of the dentists followed the prevailing instructions on oral health record keeping (82%, if partial agreement included). Most dentists (88% fully agreed, 95% at least partly) perceived that their knowledge gained through continuing education was being applied in practice; no one answered no. A gap was found between dentists' perception of the treatment rendered and everyday treatment practices as recorded on patient documents. Overall, dentists' perception of the quality of their treatment practices exceeded that found in patient documents. This gap deserves consideration while planning research, education, or quality-improvement projects that relate to dentists' opinions.


Assessing the combined effect of extremely low-frequency magnetic field exposure and oxidative stress on LINE-1 promoter methylation in human neural cells.
Extremely low frequency magnetic fields (ELF-MF) have been classified as "possibly carcinogenic", but their genotoxic effects are still unclear. Recent findings indicate that epigenetic mechanisms contribute to the genome dysfunction and it is well known that they are affected by environmental factors. To our knowledge, to date the question of whether exposure to ELF-MF can influence epigenetic modifications has been poorly addressed. In this paper, we investigated whether exposure to ELF-MF alone and in combination with oxidative stress (OS) can affect DNA methylation, which is one of the most often studied epigenetic modification. To this end, we analyzed the DNA methylation levels of the 5'untranslated region (5'UTR) of long interspersed nuclear element-1s (LINE-1 or L1), which are commonly used to evaluate the global genome methylation level. Human neural cells (BE(2)C) were exposed for 24 and 48 h to extremely low frequency pulsed magnetic field (PMF; 50 Hz, 1 mT) in combination with OS. The methylation levels of CpGs located in L1 5'UTR region were measured by MassARRAY EpiTYPER. The results indicate that exposures to the single agents PMF and OS induced weak decreases and increases of DNA methylation levels at different CpGs. However, the combined exposure to PMF and OS lead to significant decrease of DNA methylation levels at different CpG sites. Most of the changes were transient, suggesting that cells can restore homeostatic DNA methylation patterns. The results are discussed and future research directions outlined.


Utility of Homologous Recombination Deficiency Biomarkers Across Cancer Types.
Homologous recombination DNA repair deficiency (HRD) is associated with sensitivity to platinum and poly (ADP-ribose) polymerase inhibitors in certain cancer types, including breast, ovarian, pancreatic, and prostate. In these cancers, BRCA1/2 alterations and genomic scar signatures are useful indicators for assessing HRD. However, alterations in other homologous recombination repair (HRR)-related genes and their clinical significance in other cancer types have not been adequately and systematically investigated. We obtained data sets of all solid tumors in The Cancer Genome Atlas and Cancer Cell Line Encyclopedia, and comprehensively analyzed HRR pathway gene alterations, their loss-of-heterozygosity status, and per-sample genomic scar scores, that is, the HRD score and mutational signature 3 ratio, DNA methylation profiles, gene expression profiles, somatic TP53 mutations, sex, and clinical or in vitro response to chemical exposure. Biallelic alterations in HRR genes other than BRCA1/2 were also associated with elevated genomic scar scores. The association between HRR-related gene alterations and genomic scar scores differed significantly by sex and the presence of somatic TP53 mutations. HRD tumors determined by a combination of indices also showed HRD features in gene expression analysis and exhibited significantly higher sensitivity to DNA-damaging agents than non-HRD cases in both clinical samples and cell lines. This study provides evidence for the usefulness of HRD analysis in all cancer types, improves chemotherapy decision making and its efficacy in clinical settings, and represents a substantial advancement in precision oncology.A comprehensive pan-cancer analysis on the clinical significance of homologous recombination deficiency.


Mechanism of Cooperativity and Nonlinear Release Kinetics in Multivalent Dendrimer-Atropine Complexes.
Despite extensive studies on drug delivery using multivalent complexation systems, the biophysical basis for release kinetics remains poorly defined. The present study addresses this aspect involved in the complexation of a fifth generation poly(amidoamine) (PAMAM) dendrimer with atropine, an essential antidote used for treating organophosphate poisoning. First, we designed (1)H NMR titration studies for determining the molecular basis of the drug complexation with a glutarate-modified anionic dendrimer. These provide evidence pointing to a combination of electrostatic and hydrophobic interactions as the driving forces for dendrimer complexation with the alkaloid drug molecule. Second, using LC-MS/MS spectrometry, we determined the dissociation constants (KD) at steady state and also measured the drug release kinetics of atropine complexes with four negatively charged dendrimer types. Each of these dendrimers has a high payload capacity for up to ∼ 100 atropine molecules. However, the affinity of the atropine to the carrier was highly dependent on the drug to dendrimer ratio. Thus, a complex made at a lower loading ratio (≤ 0.1) displayed greater atropine affinity (KD ≈ μM) than other complexes prepared at higher ratios (>10), which showed only mM affinity. This negative cooperative variation in affinity is tightly associated with the nonlinear release kinetics observed for each complex in which drug release occurs more slowly at the later time phase at a lower loading ratio. In summary, the present study provides novel insights on the cooperativity as the mechanistic basis for nonlinear release kinetics observed in multivalent carrier systems.


A two-stage differential hydrogen deuterium exchange method for the rapid characterization of protein/ligand interactions.
The peroxisome proliferator-activated receptor is a member of the nuclear receptor superfamily of transcriptional regulators. Regulation of the nuclear receptors occurs through changes to the structure and dynamics of the ligand-binding domain. Therefore, the need has arisen for a rapid method capable of detecting changes in the dynamics of nuclear receptors following ligand binding. We recently described how solution-phase amide hydrogen/deuterium exchange (HDX) provides a biophysical technique for probing changes in protein dynamics induced by ligand interaction. Building from this platform, we have optimized the robustness of the differential HDX experiment by minimizing systematic errors, and have increased the efficiency of the chromatographic separation through the use of high-pressure liquid chromatography. Using knowledge gained previously from comprehensive HDX experiments of PPARgamma, a modest throughput method to probe changes in the dynamics of key regions of the receptor was developed. A collection of ten synthetic and endogenous PPARgamma ligands were characterized with this new method requiring approximately 24 h of analysis. This is a dramatic improvement over the 10 d of analysis that would have been required with our previous approach for comprehensive differential HDX analysis. In addition to demonstrating the utility of this approach, the study presented here is the first to measure changes to the dynamics of PPARgamma upon the binding of putative endogenous ligands.


Parents' experiences with neonatal home care following initial care in the neonatal intensive care unit: a phenomenological hermeneutical interview study.
A descriptive study of parents' experiences with neonatal home care following initial care in the neonatal intensive care unit. As survival rates improve among premature and critically ill infants with an increased risk of morbidity, parents' responsibilities for neonatal care grow in scope and degree under the banner of family-centred care. Concurrent with medical advances, new questions arise about the role of parents and the experience of being provided neonatal care at home. An interview study with a phenomenological hermeneutic approach. Parents from a Swedish neonatal (n = 22) home care setting were extensively interviewed within one year of discharge. Data were collected during 2011-2012. The main theme of the findings is that parents experience neonatal home care as an inner emotional journey, from having a child to being a parent. This finding derives from three themes: the parents' experience of leaving the hospital milieu in favour of establishing independent parenthood, maturing as a parent and processing experiences during the period of neonatal intensive care. This study suggests that neonatal home care is experienced as a care structure adjusted to incorporate parents' needs following discharge from a neonatal intensive care unit. Neonatal home care appears to bridge the gap between hospital and home, supporting the family's adaptation to life in the home setting. Parents become empowered to be primary caregivers, having nurse consultants serving the needs of the whole family. Neonatal home care may therefore be understood as the implementation of family-centred care during the transition from NICU to home.


Genocide and public health: German doctors and Polish Jews, 1939-41.
German doctors in the General Government played an important role in providing the medical rationalization for ghettoization and mass murder. Their desire to prevent the spread of disease to Germans led them to favour providing adequate health care for Poles. The same self-interest engendered their persistent advocacy of ghettoization for Jews, who were believed to be natural carriers of spotted fever. When ghetto conditions created a self-fulfilling prophecy of wide-spread disease, the doctors advocated tighter sealing of the ghettos. By late 1941, this self-induced threat to public health made the doctors receptive to a mass murder solution.


Genetic variation of Zoarces viviparus: six populations revisited after about 35 years.
Totally, 417 eelpouts from six localities were collected in November-December 2007. Among these, 314 were females and from 246 of these females, one offspring was collected. The selected populations were also studied 36-38 years ago with the same technique, horizontal starch gel electrophoresis. The same enzymes were analysed at that time and now, but additional enzymes were analysed in the samples collected now, totally five enzymes representing 10 loci. A strong congruence in the genetic composition was found between the samples collected 36-38 years ago and those collected in 2007. No effect of pollutants in the environment was seen on the genetic variation by means of isozymes, but deformed offspring was observed and furthermore at one locality a high frequency of not pregnant females in the sample was observed.


Periaqueductal gray matter modulates the hypercapnic ventilatory response.
The periaqueductal gray (PAG) is a midbrain structure directly involved in the modulation of defensive behaviors. It has direct projections to several central nuclei that are involved in cardiorespiratory control. Although PAG stimulation is known to elicit respiratory responses, the role of the PAG in the CO(2)-drive to breathe is still unknown. The present study assessed the effect of chemical lesion of the dorsolateral and dorsomedial and ventrolateral/lateral PAG (dlPAG, dmPAG, and vPAG, respectively) on cardiorespiratory and thermal responses to hypercapnia. Ibotenic acid (IBO) or vehicle (PBS, Sham group) was injected into the dlPAG, dmPAG, or vPAG of male Wistar rats. Rats with lesions outside the dlPAG, dmPAG, or vPAG were considered as negative controls (NC). Pulmonary ventilation (VE: ), mean arterial pressure (MAP), heart rate (HR), and body temperature (Tb) were measured in unanesthetized rats during normocapnia and hypercapnic exposure (5, 15, 30 min, 7 % CO(2)). IBO lesioning of the dlPAG/dmPAG caused 31 % and 26.5 % reductions of the respiratory response to CO(2) (1,094.3 ± 115 mL/kg/min) compared with Sham (1,589.5 ± 88.1 mL/kg/min) and NC groups (1,488.2 ± 47.7 mL/kg/min), respectively. IBO lesioning of the vPAG caused 26.6 % and 21 % reductions of CO(2) hyperpnea (1,215.3 ± 108.6 mL/kg/min) compared with Sham (1,657.3 ± 173.9 mL/kg/min) and NC groups (1,537.6 ± 59.3). Basal VE: , MAP, HR, and Tb were not affected by dlPAG, dmPAG, or vPAG lesioning. The results suggest that dlPAG, dmPAG, and vPAG modulate hypercapnic ventilatory responses in rats but do not affect MAP, HR, or Tb regulation in resting conditions or during hypercapnia.


Neuroimaging-guided rTMS of the left inferior frontal gyrus interferes with repetition priming.
Neuroimaging studies of right-handed normal volunteers under semantic word generation tasks have consistently reported left lateralized activation of the anterior inferior frontal gyrus (ifg) which decreased during task repetition. This repetition-related activation decrease has been interpreted as the neurophysiological correlate of repetition priming, a mechanism of implicit memory for initial semantic processing. We interfered with left lateralized ifg activation, as identified by O-15-water PET activation, using repetitive transcranial magnetic stimulation (rTMS) in five right-handed male normal subjects, once using new (unprimed) nouns and once using known (primed) nouns for the procedure. All five subjects exhibited clear left lateralized activations of the triangular part of the left ifg in the PET studies. In all subjects, reaction time latencies were significantly longer during rTMS over the activation sites in the left ifg as compared to latencies off stimulation. Latencies were not affected during stimulation of the right ifg or over the vertex. These effects were observed within the group and in each individual, only if lists of primed nouns were used in the verb-generation task. In conclusion, these results demonstrate that the anterior part of the left ifg is not only involved in semantic processing, but is also essential for repetition priming on semantic tasks since successful interference with rTMS was only observed if lists of primed words were used for the generation task.


[Effects of vinorelbine on apoptosis and expression of telomerase activity in human lung adenocarcinoma cells in vitro].
To study the effect of vinorelbine on apoptosis, telomerase activity and expression of hTERT gene in human lung adenocarcinoma cell line Anip973 cells. Anip973 cells were cocultured with Vinorelbine at different concentrations and collected at 24 h, 48 h and 72 h after treatment, respectively. The inhibition rate of cell growth was determined by methyl thiazolyl tetrazolium (MTT) assay to evaluate the effect of vinorelbine. The percentage of apoptosis was detected by flow cytometry. The cellular morphology was observed under inverted microscope and electron microscope. Telomerase activity of Anip973 cells was determined by the method of TRAP-PAGE-silver staining. RT-PCR was used to detect the expression of hTERT mRNA. Vinorelbine down-regulated the telomerase activity and expression of hTERT gene mRNA, inhibited the growth of Anip973 cells, and induced cell apoptosis in a time- and concentration-dependent manner. Annexin V-FITC assay showed 0.08 µg/ml NVB group could inhibited cell proliferation in 24 hour, and apoptosis rate was (7.37 ± 0.35)%, RT-PCR detection of hTERT mRNA expression in this group was (57.01 ± 1.71), and they were very significantly different from that in the control group (P < 0.01), but telomerase activity was (6.36 ± 0.06), compared with the control group showed no significant difference(P > 0.05). The change of hTERT mRNA expression is more sensitive than telomerase activity. The apoptosis rate, telomerase activity and hTERT mRNA expression of 0.4 µg/ml group and 2.0 µg/ml group were very significantly different from that in the control group (P < 0.01). The telomerase activity of 2.0 µg/ml at 72 hour group was (1.36 ± 0.27), basically completely inhibited, while the apoptosis rate was (74.87 ± 1.88)%, showed the cell apoptosis rate was in a negative correlation with the down-regulation of the hTERT mRNA (r = -0.96046, P < 0.01). Vinorelbine can induce apoptosis in Anip973 cells, and its mechanism of action is related to telomerase activity. The detection of telomerase activity and expression of hTERT gene is useful in predicting prognosis of patients with lung adenocarcinoma.


Consequences of Early Conductive Hearing Loss on Long-Term Binaural Processing.
The aim of the study was to investigate the long-term effects of early conductive hearing loss on binaural processing in school-age children. One hundred and eighteen children participated in the study, 82 children with a documented history of conductive hearing loss associated with otitis media and 36 controls who had documented histories showing no evidence of otitis media or conductive hearing loss. All children were demonstrated to have normal-hearing acuity and middle ear function at the time of assessment. The Listening in Spatialized Noise Sentence (LiSN-S) task and the masking level difference (MLD) task were used as the two different measures of binaural interaction ability. Children with a history of conductive hearing loss performed significantly poorer than controls on all LiSN-S conditions relying on binaural cues (DV90, p = <0.001 and SV90, p = 0.003). No significant difference was found between the groups in listening conditions without binaural cues. Fifteen children with a conductive hearing loss history (18%) showed results consistent with a spatial processing disorder. No significant difference was observed between the conductive hearing loss group and the controls on the MLD task. Furthermore, no correlations were found between LiSN-S and MLD. Results show a relationship between early conductive hearing loss and listening deficits that persist once hearing has returned to normal. Results also suggest that the two binaural interaction tasks (LiSN-S and MLD) may be measuring binaural processing at different levels. Findings highlight the need for a screening measure of functional listening ability in children with a history of early otitis media.


M3, a natural lignan xyloside, exhibits potent anticancer activity in HCT116 cells.
4-O-(2',3',4'-tri-O-methyl-β-D-xylopyranosyl) diphyllin (M3) is a cytotoxic compound that was first isolated from the aerial parts of Phyllanthus taxodiifolius. The current study demonstrated that M3, a lignan xyloside, exhibits anticancer effects in a number of cancer cell lines by MTT test, including HCT116 cells. An association was identified between M3 treatment and the reduced proliferation of cancer cells; the half maximal inhibitory concentration (IC50) value of M3 ranged from 0.08 to 1.12 µM. Furthermore, M3 was revealed to exhibit a stronger antiproliferative effect by Annexin-V-FLUOS test compared with VP-16, another natural lignan used in cancer treatment. Notably, the IC50 value of M3 with MTT test in HCT116 cells was 0.08 µM. In addition, it was revealed that M3 could induce apoptosis in HCT116 cells in a caspase-3-dependent manner at a lower concentration compared with VP-16. Further analysis identified that the antiproliferation effect of M3 was associated with the promotion of microtubule depolymerization by CytoDYNAMIX Screen 03 Tubulin Polymerization assay. In summary, the current study demonstrated that M3 could inhibit proliferation and induce apoptosis in HCT116 cells, which supports a potential therapeutic application of M3 in cancer treatment, particularly in colon cancer.


Nanosize SnO₂ confined in the porous shells of carbon cages for kinetically efficient and long-term lithium storage.
We explore a hybrid material consisting of SnO(2) nanoparticles (NPs) embedded in the porous shells of carbon cages (SnO(2)-PSCC). The hybrid material exhibits improved kinetics of lithiation-delithiation and high reversible capacity, and excellent cyclic stability without capacity loss over 100 cycles at 500 mA g(-1) with a coulombic efficiency close to 100% after the initial cycle. This can be ascribed to the high electrical conductivity, the hierarchical porosity and the confinement effect of the PSCC on the volume change of SnO(2) NPs. The material has a large reversible capacity of 460 mA h g(-1) at a high current density of 5 A g(-1) due to a short ion diffusion length in the bulk and large number of inter-pore ion transport channels. These results provide insight into improving the lithium storage performance of SnO(2) by facilitating the reaction kinetics and indicate that this hybrid material has great potential for use in high-rate and durable lithium ion batteries.


Acute hepatitis after amiodarone infusion.
Acute hepatitis is a very rare, but potentially fatal, adverse effect of intravenous amiodarone. We present a case of an 88-year-old man with history of ischemic dilated cardiomyopathy and severely depressed left ventricular function that was admitted to our coronary care unit with diagnosis of decompensated heart failure and non-sustained ventricular tachycardia. A few hours after the beginning of intravenous amiodarone he developed an acute hepatitis. There was a completely recovery within the next days after amiodarone withdrawn and other causes of acute hepatitis have been ruled out. This case highlights the need for close monitoring of hepatic function during amiodarone infusion in order to identify any potential hepatotoxicity and prevent a fatal outcome. Oral amiodarone is, apparently, a safe option in these patients.


The magnitude of precancerous cervical lesions and its associated factors among women screened for cervical cancer at a referral center in southern Ethiopia, 2021: a cross-sectional study.
Cervical cancer is the most prevalent gynecologic cancer in women and the second leading cause of cancer death worldwide. Africa's southern, eastern, and western regions have the highest rates of cervical cancer. Cervical cancer is treatable and curable when detected early, but it is nonetheless fatal in low- and middle-income (LMIC) nations where screening and early detection are not widely accessible. The objective of this study is to assess the magnitude of precancerous cervical lesions and their associated factor among women screened for cervical cancer at a referral center in southern Ethiopia, in 2021. A retrospective institution-based cross-sectional study was conducted from February 21 to April 14, 2022, among randomly selected 372 records of women screened for cervical cancer at Hawassa University Specialized Hospital. Data were extracted from clients' charts using a data extraction checklist. Statistical Package for Social Sciences version 26 and logistic regression analysis were applied to determine the association between dependent and independent variables, and significance was declared at p-value <0.05. The magnitude of abnormal cervical dysplasia in this study was 18.3% of which 14% were precancerous cervical lesions and 4.3% were cervical cancer. Early coitarche: Adjusted odds ratio (AOR) = 5.6 [95% (confidence interval) CI = 1.87-16.78], having more than one sexual partner: AOR = 2.6 [95% CI = 1.2-5.68], being HIV positive: AOR = 3.56 [95% CI = 1.53-8.29], and having sexually transmitted infections: AOR = 4.64 [95% CI = 2.08-10.35] were independent predictors of precancerous cervical lesions. The magnitude of precancerous cervical lesions in the study setting is 18% and the magnitude of cervical cancer is 14%, which is higher than the pooled prevalence of precancerous cervical lesions in Ethiopia. Having multiple sexual partners, being HIV positive, having sexual intercourse before 21 years, and new STI diagnosis was independently associated with abnormal precancerous cervical lesions.


[Penile cancer].
We review the literature on penis cancer. The disease is rare and most of the cumulative experience is reported in retrospective series. Multi-institutional international collaboration will be needed for prospective studies of certain facets of this disease which are at present controversial. Suggested areas of research are how to treat early invasive tumours, the diagnosis and treatment of inguinal metastases, the improvement of radiotherapy techniques, the development of effective chemotherapy and effective combinations of therapies. This will potentially lead to a more sparing of organs. It is also necessary to study palliation, and aspects of quality of life. The incidence may be further reduced by educating the public about the condition and about genital hygiene, including the necessity for the early treatment of phimosis.


[Casparus Fraxinus at the University of Padua].
This article, as addition to the previous ones, analyses the 16th century Hungarian physician's, Gáspár Korös' studies at the University Padoua. Giving a detailed description of the contemporary Padouan-Hungarian cultural connections, the author attempts to reconstruate the effects and circumstances this time Korös was influenced by. The author, while listing the professors, whose teaching proved to be determinative for the young Hungarian physician, refutes some mistakes based on the earlier medical historical literature. In its second part, the article focuses on the importance of the personal connections in the carreer of Korösi, who after his return to Hungary played an important role in the medical history of the country.


Evaluation of Six Split-thickness Skin Graft Donor-site Dressing Materials in a Swine Model.
Numerous dressings for split-thickness skin graft donor sites are commercially available with no conclusive evidence-based consensus regarding the optimal dressing choice. This study was conducted to identify which of 5 commonly used materials promotes wound healing most effectively for use on split-thickness donor sites in comparison with our standard dressing, Xeroform (petrolatum gauze). Twenty-four partial-thickness wounds were created on the backs of 4 pigs using a dermatome. Wounds (n = 4 per dressing type per pig) were treated with Xeroform, Opsite (polyurethane film), Kaltostat ( calcium sodium alginate), DuoDERM (hydrocolloid), Aquacel (hydrofiber), and Mepilex (silicone foam). Full-thickness skin samples were excised at 3 or 5 days and evaluated histologically for reepithelialization and inflammation. Comparisons also included incidence of infection, ease of use, and cost analyses. DuoDERM elicited the greatest percent reepithelialization (81%) and Mepilex the lowest (33%) after 3 days (P = 0.004). All dressings demonstrated complete reepithelialization except Mepilex (85%) at 5 days. There were no infections and inflammation was mild among all treatments. Mepilex was easiest to use, whereas Aquacel, Kaltostat, and Opsite were most difficult (P = 0.03). Xeroform was most cost-effective and Aquacel most expensive. Combined scoring revealed DuoDERM = Xeroform > Opsite = Mepilex > Kaltostat > Aquacel. DuoDERM and Xeroform were most effective overall. DuoDERM tended to outperform all dressings in reepithelialization at 3 days, while Xeroform was least expensive, easy to use, and demonstrated rapid reepithelialization. These findings suggest that Xeroform may be preferred for use on large donor-site areas. DuoDERM may be more appropriate for small donor sites when healing time is a priority.


Use of ionic currents to identify and estimate parameters in models of channel blockade.
Models of ion channel blockade are frequently validated with observations of ionic currents resulting from electrical or chemical stimulation. Model parameters for some models (modulated receptor hypothesis) cannot be uniquely determined from ionic currents. The time course of ionic currents reflects the activation (fraction of available channels that conduct in the presence of excitation) and availability of channels (the ability of the protein to make a transition to a conducting conformation and where this conformation is not complexed with a drug). In the presence of a channel blocking agent, the voltage dependence of availability appears modified and has been interpreted as evidence that drug-complexed channels exhibit modified transition rates between channel protein conformations. Because blockade and availability both modify ionic currents, their individual contributions to macroscopic conductance cannot be resolved from ionic currents except when constant affinity binding to a bindable site is assumed. Experimental studies of nimodipine block of calcium channels and lidocaine block of sodium channels illustrate these concepts.